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Histamine H₃ receptor inverse agonists are known to enhance the activity of histaminergic neurons in brain and thereby promote vigilance and cognition. 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride (BF2.649) is a novel, potent, and selective nonimidazole inverse agonist at the recombinant human H₃ receptor. On the stimulation of guanosine 5′-O-(3-[³⁵S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a K_i value of 0.16 nM and as an inverse agonist with an EC₅₀ value of 1.5 nM and an intrinsic activity ∼50% higher than that of ciproxifan. Its in vitro potency was ∼6 times lower at the rodent receptor. In mice, the oral bioavailability coefficient, i.e., the ratio of plasma areas under the curve after oral and i.v. administrations, respectively, was 84%. BF2.649 dose dependently enhanced tele-methylhistamine levels in mouse brain, an index of …